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TNFR1 Expressing Exosomes are Critical Mediators of Pathological Immune Activation in the Spleen post-Myocardial Infarction

表达 TNFR1 的外泌体是心肌梗死后脾脏病理性免疫激活的关键介质

基本信息

批准号：
10483212
负责人：
Shyam Sunder Bansal
金额：
$ 55.24万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-07 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10483212
关键词：
Adoptive Transfer Animal Model Antigen-Presenting Cells Antigens Biology Blood Circulation Bone Marrow Breeding CD4 Positive T Lymphocytes Cardiac Cardiac Myocytes Cardiovascular system Cells Clinical Clinical Research Complex Congestive Heart Failure Data Dendritic Cells Disease Progression Distant Dyes EFRAC Echocardiography Eotaxin Fibrosis Functional disorder Gene Expression Heart Heart Injuries Heart failure Hypertrophy Hypoxia Immune Immune response Immunology Immunotherapeutic agent Incubated Infarction Infiltration Inflammation Inflammatory Injections Knowledge Label Left Left Ventricular Remodeling Left ventricular structure Letters Ligation Lymphoid Lymphoid Tissue Measures Mediating Mediator of activation protein Membrane Messenger RNA MicroRNAs Mitochondrial Proteins Molecular Mus Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Operative Surgical Procedures PKH 26 Pathologic Physiological Proteins Regulatory T-Lymphocyte Role S100A8 gene S100A9 gene Scientist Severities Signal Transduction Signaling Molecule Signaling Protein Source Spleen Splenocyte T memory cell TNFRSF1A gene Testing Tissues Tumor Necrosis Factor Receptor Ventricular Vesicle base cell type cellular targeting exosome experience healing heart function hematopoietic tissue immune activation immunogenic immunoregulation intercellular communication intravenous administration intravenous injection ischemic injury macrophage monocyte preclinical study prevent response tool trafficking wound healing

项目摘要

Project Summary Immune activation is a hallmark of myocardial infarction (MI) and dictate infarct healing and left ventricular (LV) remodeling. It is established, both in preclinical and clinical studies, that immediately after infarction immune cells from the spleen and the bone-marrow (BM) egress into the systemic circulation and traffic to the ischemic hearts. This suggests that the damage signals from the injured hearts are communicated to the lymphoid and the hematopoietic tissues to initiate cardiac-specific immune responses. However, the mechanisms by which these signals are transferred to the immune-rich niches such as the spleen are not known. Recent studies have shown that exosomes, membranous vesicles of 30-100 nm size, are potent intercellular communication vehicles that can shuttle mRNA, miRNA, and proteins to the distant tissues for physiological and pathological immune activation. It is also known that circulating exosomal levels increase during myocyte damage and contain sarcomeric, cytosolic and mitochondrial proteins in their cargo. Despite this understanding, it is not known if exosomes also serve as the antigenic vehicles to carry damage- associated protein signals from the ischemic myocardium to the spleen for subsequent immune activation. Indeed, our preliminary results clearly show that intravenous administration of exosomes released by the ischemic hearts (as compared to sham) into the naïve mice induce i) systolic dysfunction (increased end- diastolic and end-systolic volumes and decreased ejection fraction), ii) gene expression of damage associated signals (S100A8, S100A9 and eotaxin) in the left-ventricles, iii) splenic remodeling, and iv) infiltration of innate and adaptive immune cells in the myocardium. Moreover, MI exosomes expressed tumor necrosis factor receptor-1 (TNFR1; and not TNFR2) on their membranes, a classical pro-inflammatory signaling molecule that have been shown to correlate with HF severity and cardiac dysfunction clinically. Importantly, intravenous injection of exosomes isolated from 1d MI TNFR1-/- mice failed to induce cardiac dysfunction in naïve mice suggesting a potent, and previously unknown, role of exosomal TNFR1 in mediating immune activation post-MI and cardiac dysfunction. Therefore, this led us to hypothesize that exosomes carry cardiac antigens to mediate splenic immune cell activation during MI, are critical for immune cell mediated pathological LV remodeling, and these effects are dependent upon the exosomal TNFR1 expression. Importantly, these are key cellular targets for immunomodulation. We will test this hypothesis by i) determining the pathophysiological role of the spleen in mediating exosomal processing post-MI, ii) defining the source and role of vesicular TNFR1 in exosome mediated cardiac dysfunction, and iii) determining the role of exosomal TNFR1 in mediating immunogenic signaling.

项目总结